Dabrafenib Active in Rare NSCLC Subtype

According to results from a phase II study, the BRAF inhibitor dabrafenib (Tafinlar; GlaxoSmithKline) has significant single-agent activity in patients with advanced non–small cell lung cancer (NSCLC) harboring the BRAF V600E mutation. However, combining this drug with a MEK inhibitor may be a more effective treatment strategy, based on preliminary data from another arm of the same study.

Dabrafenib is currently approved for unresectable or metastatic BRAF V600E–positive melanoma. This mutation is rarer in NSCLC, being present in about 2% of cases.

Eighty-four patients—78 of whom had received at least one prior therapy and six of whom hadn't received any treatment—were enrolled in the study's dabrafenib-only arm. The objective response rates (ORR) for previously treated and untreated patients were 33% and 67%, respectively. The drug's overall toxicity profile was comparable to that of standard chemotherapy, investigators reported. Its main side effect, cutaneous squamous-cell carcinoma, occurred in 42% of patients.

“Dabrafenib is about three times more active than standard docetaxel in previously treated patients,” says senior author Bruce Johnson, MD, chief clinical research officer at Dana-Farber Cancer Institute in Boston, MA. “Additionally, progression-free survival was about 5.5 months, which is twice as long as we've seen with chemotherapy.”

However, Johnson points out that the ORR of 33% for previously treated patients is significantly lower than that seen with other targeted agents for NSCLC. Data from another arm of the study suggest that combining dabrafenib with the MEK inhibitor trametinib (Mekinist; GlaxoSmithKline) may be more effective: Preliminary results reported last year showed an ORR of 63% in previously treated patients, prompting the FDA to grant Breakthrough Therapy status to this combination.

Dabrafenib causes activation of MEK, which is downstream of BRAF along the MAPK pathway. This may be why it's more effective combined with trametinib, Johnson explains. The combination may also reduce the incidence of skin cancers, which can be triggered by MAPK pathway activation, he adds. The investigators plan to present updated results from the study's combination arm at the American Society of Clinical Oncology annual meeting in June.

Although this trial suggests that dabrafenib is superior to chemotherapy, patients with BRAF-mutant NSCLC should look to enroll in studies testing combination therapies, notes Julian Molina, MD, PhD, an oncologist at the Mayo Clinic in Rochester, MN.

“These patients have very limited treatment options,” he says. “At this point, we have preliminary evidence suggesting that the combination of dabrafenib and trametinib seems to be more effective and has a better scientific rationale than single-agent therapy.” –Janet Colwell